K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation.
The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger-type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase-like proteins Sts1 and ... Sts2 and thereby terminated early TCR signaling in CD8(+) T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8(+) T cells but not that of naive CD4(+) T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.
Mesh Terms:
Animals, CD8-Positive T-Lymphocytes, Carrier Proteins, Lymphocyte Activation, Lysine, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Phosphorylation, Polyubiquitin, Protein Binding, RNA Interference, Receptors, Antigen, T-Cell, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcriptome, Ubiquitination, ZAP-70 Protein-Tyrosine Kinase
Animals, CD8-Positive T-Lymphocytes, Carrier Proteins, Lymphocyte Activation, Lysine, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Phosphorylation, Polyubiquitin, Protein Binding, RNA Interference, Receptors, Antigen, T-Cell, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Transcriptome, Ubiquitination, ZAP-70 Protein-Tyrosine Kinase
Nat. Immunol.
Date: Dec. 01, 2015
PubMed ID: 26390156
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